Fatigue-resistant flow regulating device and manufacturing methods

ABSTRACT

The subject invention is directed to devices and methods for producing devices for regulating blood flow in the venous system. In particular, the invention provides for artificial valves designed to regulate the flow of blood in human vessels, wherein such artificial valves include superior properties including fatigue resistance, biocompatibility, and ease of manufacture.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.13/635,589, now U.S. Pat. No. 9,801,737, filed Dec. 27, 2012, which is anational stage entry of PCT/US2011/027724, with an international filingdate of Mar. 9, 2011, which claims priority to U.S. Provisional PatentApplication No. 61/314,699, filed Mar. 17, 2010, the entire contents ofeach of which are incorporated by reference herein in their entireties.This application incorporates by reference herein each of the followingcommonly assigned U.S. patent applications in its entirety: applicationSer. No. 12/713,476 filed Feb. 26, 2010, application Ser. No. 12/319,176filed Jan. 2, 2009, application Ser. No. 11/801,691 filed May 10, 2007,and application Ser. No. 11/801,489 filed May 10, 2007.

BACKGROUND OF THE INVENTION 1. Field of the Invention

The subject invention is directed to devices for regulating blood flowin the venous system, and more particularly, to the design andproduction of artificial valve devices designed to regulate the flow ofblood in human vessels.

2. Description of Related Art

Artificial venous valves offer numerous possibilities that can be veryattractive to clinicians and patients. Benefits of such designs include,the possibility of improved functional stability and life while reducingsize and bulk of the valve, which offers opportunities forinterventional, less traumatic procedures for valve placement. In spiteof the existence of a great number of artificial valve designs, very fewof them have managed to pass through clinical trials and make it to theclinical arena.

Today's use of artificial valves is limited to relatively bulkymechanical valves or tissue based valves. The reason for this is thatsmall and compact valves, suitable for interventional applications,require the use of thin metal frames and ultra thin polymer parts joinedtogether, to meet the harsh requirements of a multimillion cycleapplication in blood flow. Herein is the main problem of percutaneouslyinserted valves—their mechanical designs, historically, have not provento be as robust as that of bulkier valves, and have been prone tobiocompatibility, long term stability, wear and fatigue issues.

Such conventional methods and systems have generally been consideredsatisfactory for their intended purpose. However, there is still a needin the art for artificial valves that allow for improved fatigueresistance. There also remains a need in the art for such artificialvalves that are easy to make and use. The present invention provides asolution for these problems.

SUMMARY OF THE INVENTION

The subject invention is directed to new and useful artificial valves.The applications incorporated by reference above generally providemechanical design details. This application is more particularlydirected to the issues of valve material compatibility, stability anddurability by material selection and manufacturing techniques used toaddress the specific requirements of fatigue related to the imbalance ofstresses between metal parts and elastic polymer components, by:

-   Selecting optimal, proven materials designed to perform in this    harsh environment,-   Reducing stress concentrations at the interfaces between materials    having radically different stiffness and modulus of elasticity,-   Reducing friction between component joints, and-   Increasing tear resistance of the polymer components.

These and other features of the systems and methods of the subjectinvention will become more readily apparent to those skilled in the artfrom the following detailed description of the preferred embodimentstaken in conjunction with the drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

So that those skilled in the art to which the subject inventionappertains will readily understand how to make and use the apparatus ofsubject invention without undue experimentation, preferred embodimentsthereof will be described in detail hereinbelow with reference tocertain figures, wherein:

FIG. 1 is a perspective view of the flow regulating device of thepresent invention, prior to full assembly;

FIG. 2 is a perspective view of the support of the flow-regulatingdevice of FIG. 1;

FIG. 3 is a side perspective view of the flow regulating deviceillustrating how the membrane is attached to the frame;

FIG. 4 is a front perspective view of the top (distal) portion of theflow regulating device of FIG. 1 showing the membrane in the closedposition;

FIG. 5A is a side perspective view showing the membrane in the openposition;

FIG. 5B is a side perspective view similar to FIG. 5A showing themembrane in the closed position;

FIG. 6A is a cross-sectional view of the identified area of FIG. 5Ashowing the membrane in the open position, resulting from antegradeblood flow;

FIG. 6B is a cross-sectional view of the identified area of FIG. 6Ashowing the membrane in the closed position, resulting from retrogradeblood flow;

FIG. 6C is a top view of the upper region of the membrane of FIG. 5Bshowing the membrane in the closed position;

FIG. 6D is a top view of the upper region of the membrane of FIG. 5Ashowing the membrane in the open position;

FIG. 6E is a top view of the upper region of another exemplaryembodiment of the membrane shown in the open position;

FIG. 7 is a view similar to FIG. 4 showing another exemplary embodimentof the membrane with flaps forming larger openings for increasedantegrade blood flow;

FIG. 7A is a cross-sectional view similar to FIG. 6B except showing themembrane of FIG. 7 in the closed position;

FIG. 8 is a drawing of the anatomy of the patient showing two examplesof locations of placement of the flow regulating device;

FIG. 9 is a front elevation view of the frame of a flow-regulatingdevice constructed in accordance with another embodiment of the subjectinvention with the membrane or sail removed for clarity;

FIG. 10 is a side elevation view of the frame of FIG. 9, showing one ofthe symmetrical x-shaped linking members connecting the two axiallyspaced apart ring portions;

FIG. 11 is a perspective view of the frame of FIG. 9, showing both ofthe symmetrical x-shaped linking members;

FIG. 12 is a front elevation view of the flow-regulating device of FIG.9, showing the membrane or sail in place;

FIG. 13 is a side elevation view of the flow-regulating device of FIG.12, showing one of the symmetrical x-shaped linking members connectingthe two axially spaced apart ring portions with the membrane or sailattached to a portion of the cross members of the x-shaped linkingmember; and

FIG. 14 is a perspective view of the flow-regulating device of FIG. 12,showing both of the x-shaped linking members with the membrane or sailin place in the flow restricting position.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Reference will now be made to the drawings wherein like referencenumerals identify similar structural features or aspects of the subjectinvention. For purposes of explanation and illustration, and notlimitation, a partial view of an exemplary embodiment of an artificialvalve in accordance with the invention is shown in FIG. 1 and isdesignated generally by reference character 10. Other embodiments ofvalves in accordance with the invention, or aspects thereof, areprovided in FIGS. 2-14, as will be described. The system of theinvention can be used to improve performance and manufacturing ofartificial valves.

Regulating device 10 includes an elongated support 12 that has upper andlower substantially annular ring portions 14 and 24, each having aseries of rounded V-shaped apices 15 a facing in an upward direction anda series 15 b facing in a downward direction. That is, the upper ordistal (with respect to the direction of blood flow) ring portion 14 hasa first series of angled struts 13 a forming a V and a second series ofangled struts 13 b forming an inverted V which together form a group ofclosed substantially diamond shaped cells 19 connected at region 17.Similarly, the lower or proximal (with respect to the direction of bloodflow) ring portion 24 has a first series of angled struts 29 a and asecond series of angled struts 29 b, facing in opposite directions andforming closed substantially diamond shaped cells 28 connected at region27. The cells 28 have upper apices 25 and lower apices 26. For clarity,not all of the identical parts in the drawings are labelled. Note thatin the preferred embodiment, the rings and linking member (describedbelow) are preferably integral so that terms “joined”, “connected”, etc.are used for ease of description.

Support 12 has two curved linking or connecting members 21 a, 21 b, bestshown in FIG. 2 in which the membrane is removed for clarity. The top ofeach connecting member 21 a, 21 b extends from a common lower apex 15 bof one of the pairs of angled struts 13 b of upper ring 14 (see alsoFIGS. 3 and 4) The lower end of connecting members 21 a, 21 b extendfrom separate upper apices 25 a, 25 b, respectively, of cells 28 oflower ring 24. In the illustrated embodiment, the apices 25 a, 25 b, areabout 36 degrees apart as ten cells are formed. However, a differentnumber of cells can be provided with different spacing between apices.Also, it should be appreciated that the connecting members can extendfrom other apices of lower ring 24 or upper ring 14. The connectingmembers 21 a, 21 b have a curve or twist extending close to about 180degrees (and extending substantially across the vessel when implanted)so that an upper end is connected to one end (viewedradially/transversely) of the device 10 and the lower end is connectedto an opposite end (viewed radially/transversely) of the device 10. Thatis, with ten closed cells in the illustrated embodiment, apex 15 b isapproximately 162 degrees out of phase from apex 25 a and from apex 25b. Other spacing and alternate number of cells is also contemplated.

Although two connecting members are shown, one connecting member or moreconnecting members could be provided. Also, the connecting members couldbe spaced further or closer apart and have different curves than shown.

The rings 14, 24 are collapsed to a reduced diameter (profile) positionfor delivery. The rings 14, 24, when implanted, are substantiallyperpendicular to the direction of blood flow. Preferably, the rings 14,16 in their expanded (deployed) configuration are larger in diameterthan the internal diameter of the target vessel to apply a sufficientradial force against the vessel to ensure that the device remains in adesired position and orientation after implantation. For example, foruse in an 8 mm vessel, the rings could have an expanded outer diameterof about 10 mm and preferably could be collapsed sufficiently to bedelivered through a 12 Fr (4 mm) delivery catheter. Others ringdiameters are also contemplated.

The support 12 is preferably composed of shape memory material, such asNitinol or Elgitoy, with a shape memorized larger diameter configurationas shown in the drawings. In the illustrated embodiment, the support islaser cut from a tube so that the connecting members and rings areintegral. However, it is also contemplated that alternatively thesupport can be formed from wire(s). Also, it should be appreciated thatinstead of being integral, separate members could be provided, withseparate rings joined by separate linking (connecting) members.

Device 10 includes a valve member or membrane 50 that is operativelyassociated with support 12 for regulating the flow of blood through avessel by moving between open and closed positions. Membrane 50 ispreferably formed from a sheet of ultra thin membrane material such as aePTFE material or the like. It is envisioned that the membranesdisclosed herein could be bonded or otherwise coated with ananti-blotting or anti-coagulant/anti-thrombogenic agent such as Heparinand/or an anti-proliferative coating, to retard the body's desire toreject the implant. In a preferred embodiment, the membrane is coatedwith an anti-thrombogenic agent and the frame is coated with ananti-proliferative agent, such as Dexamethasone by way of example.

As shown, valve membrane 50 has an upper portion 52, an intermediateportion 62, and a lower portion 72. With reference to FIG. 3 whichillustrates how the membrane 50 is attached to support 12 inmanufacture, the top portion 52 has first and second flaps 54, 56 whichare folded down over respective connecting members 21 a, 21 b andattached to the membrane to secure the upper portion 52 of membrane 50about the support 12. FIG. 3 illustrates flap 56 already folded in thedirection of arrow F4 from its unfolded position shown in phantom. FIG.3 also illustrates flap 54 in its unfolded position before movement inthe direction of arrow F3 in manufacture to its folded position depictedin phantom. Flaps 57 and 59 at the uppermost region of membrane 50 arewrapped around struts 13 b in the direction of arrows F1, F2,respectively.

With continued reference to FIG. 3, the intermediate portion 62 ofmembrane 50 has flaps 64, 66 for connection to linking (connecting)members 21 a, 21 b, respectively. Flap 64 is shown in a mostly unfoldedposition to be folded in the direction of arrows F6 to its foldedposition shown in phantom where it is attached to the membrane 50. Flap66 is shown in its unfolded position to be folded in the direction ofarrows F5 to its folded position depicted in phantom.

Lower portion 72 of membrane 50 has flaps 74 and 76 which are eachfolded around a separate strut 29 a. Arrows F8, F7, respectively,illustrate the direction of the fold.

Cuts in the membrane 50 create an unattached flap 84 between upperattached flap 54 and intermediate attached flap 64 and an unattachedflap 86 between upper attached flap 56 and intermediate attached flap66. These unattached flaps 84, 86 are positioned adjacent the respectiveconnecting member 21 a, 21 b as shown, but create a respective opening90, 91 for blood flow between the membrane 50 and connecting members 21a, 21 b as described below. Note, alternatively, the flaps 84, 86 canextend over the connecting member, as long as it remains unattached andcreates a sufficient space from the linking member to create asufficiently sized opening to allow blood flow therethrough.

Note that FIG. 1 shows the membrane 50 with the flaps open, prior toconnection in manufacture, to illustrate how it is wrapped around thesupport 12 and connected to other portions of the membrane forsecurement/attachment of the membrane to the support 12. The flaps,after wrapping over/around the region of support 12, can be connected tothe membrane body by welding, adhesive, suturing or other methods. Also,an intermediary material can be used to facilitate welding, such aspolyurethane or polycarbonate/polyurethane impregnated or otherwisecombined with the ePTFE material. It is also contemplated that themembrane can be attached to the support 12 itself by methods such as byadhesive or use of suture material.

As can be appreciated, the body portion of the membrane 50 extendssubstantially if not entirely across the expanse of the vessel in theopen position. However, the openings 90 and 91 adjacent the unattachedflaps 84, 86 provide a sufficient gap for the necessary amount of bloodflow, it being appreciated by applicants that a normally functioningvalve is only open about 35%. In some embodiments, the openings in themembrane created by the space between flaps 84, 86 and the supportcreate a space gap in the range of about 5% to about 15% of the diameterof the vessel. In the alternate embodiment depicted in FIG. 7, largeropenings 90′ and 91′ are formed to allow more antegrade blood flow. Inthese large opening embodiments, a space (opening) can be createdpreferably representing about 15% to about 45%, and more preferably fromabout 15% to about 30% of the diameter of the vessel. (In all otherrespects the regulating device of FIG. 7 is identical to that of FIG. 4and the corresponding parts are labelled by numerals with a primedesignation and therefore are not discussed herein). These percentagesare defined in terms of the diameter of the blood vessel. For example,if a rectangular opening is formed of dimension of 2 mm×4 mm, and isplaced in a 10 mm vessel, the cross section occupied by the two openings(about 16 mm) would be about 20% of the overall diameter of the vessel(about 78 mm). It should be appreciated that the foregoing ranges andpercentages are provided by way of example and other size openingscreating a different percentage opening are also contemplated. Also,other shape openings can be provided other than rectangular, includingsquare, semicircular, etc. FIG. 6E shows by way of example substantiallysemicircular openings 90″, 91″ formed by flaps 84″, 86″, respectively.

Movement of the membrane 50 between an open (blood flow enabling)position/condition to allow antegrade blood flow and a closed (bloodflow inhibiting position/condition) to essentially block flow are shownin respective FIGS. 5A and 5B, and shown in more detail in FIGS. 6A-6D.In the closed position, however, a minimal amount of blood flow isallowed as will be discussed below.

More specifically, and with reference to FIG. 5A, blood flowing throughthe blood vessel V in the downstream direction (antegrade flow)indicated by arrow “D” will act against the valve membrane 50 in such amanner as to push the body portion upwardly as viewed in the drawing,creating a concave belly on the underside. The blood will travel alongthe concave surface and up the membrane and the blood pressure willforce the flaps 84 and 86 upwardly, separating (spreading) them from therespective connecting members 21 a, 21 b as also shown in FIGS. 6A and6D to form an opening or gap.

After the pulsed blood travels in the direction of arrow D1 (FIG. 5A),through the openings (spaces) 90, 91, the blood backs up in thedirection of arrow C of FIG. 5B. This retrograde blood flow will actagainst the angled body of the membrane 50, forcing it downwardly asviewed in FIG. 5B to form a convexity on its underside. This downwardpressure will force flaps 84, 86 downwardly adjacent to the connectingmembers 21 a, 21 b, respectively, and against the connecting member asshown for example in FIGS. 6B and 6C, thus essentially closing theopenings 90, 91 to prevent blood flow therethrough. However, a smallamount of blood will force its way between the membrane 50 and thevessel wall as depicted by arrow C1 in FIG. 5B, thereby reducing stasisor stagnation that could lead to clotting. In embodiments wherein alarger flap is utilized to create a larger opening, such as in theembodiment of FIG. 7, the flap 84′ (and 86′, not shown) in the closedposition would lie adjacent the connecting members, and extendunderneath the connecting member (e.g. connecting member 21 a′) to lieagainst the vessel wall as shown in FIG. 7A, thereby inhibiting bloodflow.

It should be appreciated that the membrane extends at an angle acrossthe vessel of about 50 to about 70 degrees to help direct the blood flowand continuously wash the membrane body to prevent blood stagnation.(Other angles are also contemplated) More specifically, blood contactingthe body portion of the membrane 50 in the open position will bedirected upwardly, along the concave surface, thereby washing themembrane body to wash away clots to reduce the likelihood of clotting.In the closed position, blood contacting the membrane body will bedirected downwardly along the angled body to wash the opposing side ofthe membrane to likewise reduce the likelihood of clotting.

As can be appreciated, the membrane 50 remains at substantially the sameangle across the blood vessel in the open (flow allowing) and closed(flow inhibiting) positions/conditions. That is, as shown in FIGS. 5Aand 5B, the upper region of the membrane 50 is adjacent one side of thevessel wall in the open (flow allowing) position. The upper regionremains adjacent the same wall in the closed (flow inhibiting) position.Similarly, the lower region of the membrane 50 is adjacent an oppositeside of the vessel wall, and remains adjacent that wall in both the openand closed positions of FIGS. 5A, 5B, respectively. Thus, the upper andlower attached regions of the membrane remain in substantially the sameposition.

One example of the location of placement of the flow regulating devicein a patient's leg is shown in FIG. 8 with areas A1 and A2 showingpossible placement sites of the device, e.g. upstream or downstream ofthe native valve V.

If composed of shape memory, the device will automatically expand to theposition shown either upon release from a delivery member or in responseto temperature change. However, if composed of other materials, thedevice can be designed to automatically expand due to the springiness ofthe material or can alternatively be implanted in a blood vessel using aballoon catheter (not shown) as described in copending U.S. patentapplication Ser. No. 11/801,691, the entire contents of which areincorporated herein by reference. That is, rings 14 and 24 can be movedfrom a closed position to an expanded position by inflating the balloonor by use of a mechanical expander. Upon expansion, the rings 14 and 24apply a force against the vessel wall, thereby being retained therein.The balloon or mechanical expander is then deflated and the catheter isremoved from the blood vessel so the device 10 can regulate the flow ofblood through the vessel in the manner described above.

In the embodiments disclosed herein showing substantially circularrings, it should be understood that the rings can be shaped to have asize larger than the diameter of the vessel and therefore, depending onthe size of the vessel, may not assume a circular shape but have an ovalshape pressing against the vessel wall toward a circular configuration.

Referring now to FIGS. 9-11, there is shown a frame for a flowregulating device constructed in accordance with another preferredembodiment of the subject invention, and designated generally byreference numeral 200. Regulating device 200 includes an elongated frame220 that consists of upper and lower substantially annular ring portions240 and 260, much as described above. Rings 240 and 260 are connected toone another by at least one connective member 280 in the form of anx-shaped bar or wire. In the exemplary embodiment of FIGS. 9-14, twox-shaped connective members 280 are shown. Connective members 280 areadapted and configured to follow the circumference of the host vessel.The individual cross-linked bars or wires of each x-shaped connectivemember 280 are attached to the opposed rings 240 and 260 of frame 220 atlocations that are about 180° apart from one another, making device 200substantially symmetrical. This gives frame 220 an inherent symmetricalflexibility and enables it to move with the natural movements (e.g.,pulsitile) of the vein.

FIGS. 12-14 show device 200 with the membrane, much as described above,in place. Membrane or sail 250 attaches to portions of the x-shapedconnective members 280. Apertures 270 allow blood flow in one direction,and inhibit flow in the opposite direction much as described above. Thisframe and sail configuration gives device 200 more support and symmetry,allows for delivery using a simpler delivery device, distributes stressmore evenly and reduces stress raisers between support portions.

The frame, described in the above and in the applications incorporatedby reference above, can be made of a laser cut, heat set, smoothlymicro-polished one piece Nitinol construct, a well known and welltolerated super elastic alloy, used for many years in the vasculatureand more recently proven to be successfully implanted within the targetvalve anatomical location. See, e.g., Neglen et al, Journal of VascularSurgery November 2007, which is incorporated by reference herein in itsentirety.

The valve membrane or leaflet, as described above and in theapplications incorporated by reference above, can be manufactured froman ePTFE (expanded polytetrafluoroethylene), which is a material with along history of being well tolerated in the vasculature. This ePTFEleaflet is designed and built to have specific stress relieved andannealed characteristics and specific porosity designed to allowattachment and adherence of the attachment polymer, while maintainingthe mechanical, functional, stability and biocompatibility requirementsfor this specific application, as described in further detail below.

The practical assembly of this device is based on a unique heat shapingprocess of the leaflet material combined with the micro thin applicationand impregnation of a proven biocompatible polycarbonate polyurethanematerial to the underside with respect to the orientation of FIG. 3 ofthe leaflet in the seam area enabling the application of heat toseamlessly attach the leaflet to the frame, via the folding describedabove and in the applications incorporated by reference above.

These attachment techniques allow the polymer material to be attached tothe frame without any perforation of the leaflet material (perforationsof a thin polymer sheet under frequent cyclic movement lead to thepotential for accelerated risk of tear propagation of the polymer sheet,as demonstrated in other medical device applications where tears wereseen at suture hole locations after cyclical use).

The folding processes described above and in the applicationsincorporated by reference above can additionally include some or all ofthe following:

1. Spraying the metal frame of the valve with silicone lubricant, toprevent adherence of the leaflet to the frame through the heat-weldingprocess;

2. Wrapping the leaflet around the frame and welding of the leafletmaterial to itself, forming a continuous flexible seam around the metalframe, without the leaflet material being adhered to the frame;

3. Using a pre-shaped bi-axially stress relieved and annealed ePTFEmaterial with the porosity range selected between 15 and 25 microns,these size pores are large enough to allow deep and uniform penetrationof a Polycarbonate polyurethane adhesive, and/or other suitableadhesive, into the bulk of the leaflet; but small enough to preventblood seepage through the leaflet;

4. Forming the leaflet from a thermally-fitted and fully annealedpolymer sheet, reducing the risk of folds and creases in the leafletthat could harbor cellular adherence;

5. Melting the thinly applied and impregnated Polycarbonate polyurethane(the strongest and most flexible of the polyurethane elastomers), tosmooth out the seam making it virtually invisible, reducing thepotential for blood or cellular adherence; and

6. Using a pre-programmed laser cutting apparatus, and/or other suitabledevice, to cut out openings in the leaflet, to allow blood flow thoughthe valve, as described in the applications incorporated by referenceabove. Laser cutting of the leaflet material causes the cut edge to besealed and lowers the risk of the cut edge having the potential fortearing or ripping during use.

The methods and systems of the present invention, as described above andshown in the drawings, provide for flow regulating devices with superiorproperties including fatigue resistance, biocompatibility, and ease ofmanufacture. While the apparatus and methods of the subject inventionhave been shown and described with reference to preferred embodiments,those skilled in the art will readily appreciate that changes and/ormodifications may be made thereto without departing from the spirit andscope of the subject invention.

What is claimed is:
 1. A method of making an implantable device forregulating blood flow through a blood vessel, comprising: a) forming anelongated support dimensioned and configured to be implanted in a bloodvessel, the support including axially spaced apart first and secondsubstantially annular support portions, and a linking member linking theaxially spaced apart portions to one another; b) forming a valvemembrane configured for extending between the axially spaced apartsupport portions, the valve membrane including a first region, a secondregion, and a flap adjacent the first region, and the second regionbeing adjacent the first region and configured to be unattached to thelinking member and movable between a first position to enable blood flowand a second position to inhibit blood flow; c) folding the flap overthe linking member for attachment to the first region of the valvemembrane for attachment of the valve membrane to the linking member; d)impregnating at least one of the flap and the first region of the valvemembrane with an impregnation material; e) joining the flapsubstantially seamlessly to the first region of the valve membrane byheat shaping at least one of the flap and the first region to form anadhesion region joining the flap and the first region together, whereinthe adhesion region includes the impregnation material; and f) sprayingthe support with silicone lubricant, to prevent adherence of the valvemembrane to the support during the joining step.
 2. A method of makingan implantable device for regulating blood flow through a blood vessel,comprising: a) forming an elongated support dimensioned and configuredto be implanted in a blood vessel, the support including axially spacedapart first and second substantially annular support portions, and alinking member linking the axially spaced apart portions to one another;b) forming a valve membrane using a pre-shaped bi-axially stressrelieved and annealed ePTFE material with the porosity range selectedbetween 15 and 25 microns and configured for extending between theaxially spaced apart support portions, the valve membrane including afirst region, a second region, and a flap adjacent the first region, andthe second region being adjacent the first region and configured to beunattached to the linking member and movable between a first position toenable blood flow and a second position to inhibit blood flow, whereinthe valve member comprises c) folding the flap over the linking memberfor attachment to the first region of the valve membrane for attachmentof the valve membrane to the linking member; d) impregnating at leastone of the flap and the first region of the valve membrane with animpregnation material; e) joining the flap substantially seamlessly tothe first region of the valve membrane by heat shaping at least one ofthe flap and the first region to form an adhesion region joining theflap and the first region together, wherein the adhesion region includesthe impregnation material.
 3. A method as recited in claim 2, whereinthe support is formed at least in part from a one piece Nitinolconstruct.
 4. A method as recited in claim 2, wherein the impregnationmaterial includes a biocompatible polycarbonate polyurethane material.5. A method as recited in claim 2, wherein the folding and joining stepsinclude wrapping the flap around the support and welding of the valvemembrane material to itself at the flap and first region, and forming acontinuous flexible seam around the support, without the valve membranebeing adhered to the support.
 6. A method as recited in claim 2, whereinthe step of joining includes melting the impregnation material to smoothout the adhesion region making the adhesion region substantiallyseamless, reducing potential for blood or cellular adherence thereto. 7.A method of making an implantable device for regulating blood flowthrough a blood vessel, comprising: a) forming an elongated supportdimensioned and configured to be implanted in a blood vessel, thesupport including axially spaced apart first and second substantiallyannular support portions, and a linking member linking the axiallyspaced apart portions to one another; b) forming a valve membraneconfigured for extending between the axially spaced apart supportportions, the valve membrane including a first region, a second region,and a flap adjacent the first region, and the second region beingadjacent the first region and configured to be unattached to the linkingmember and movable between a first position to enable blood flow and asecond position to inhibit blood flow, wherein the step of forming thevalve membrane includes using a pre-programmed laser cutting apparatusto cut out openings in the valve membrane for allowing blood flow thoughthe implantable device; c) folding the flap over the linking member forattachment to the first region of the valve membrane for attachment ofthe valve membrane to the linking member; d) impregnating at least oneof the flap and the first region of the valve membrane with animpregnation material; e) joining the flap substantially seamlessly tothe first region of the valve membrane by heat shaping at least one ofthe flap and the first region to form an adhesion region joining theflap and the first region together, wherein the adhesion region includesthe impregnation material.